Constitutive/Hypoxic Degradation of HIF-α Proteins by the Proteasome Is Independent of von Hippel Lindau Protein Ubiquitylation and the Transactivation Activity of the Protein

Xianguo Kong,Jaime Caro,Zhao Lin,Beatriz Alvarez-Castelao,José G Castaño

doi:10.1074/jbc.m700704200

Abstract

Constitutive/Hypoxic Degradation of HIF-α Proteins by the Proteasome Is Independent of von Hippel Lindau Protein Ubiquitylation and the Transactivation Activity of the Protein

Highlights

15498 JOURNAL OF BIOLOGICAL CHEMISTRY ubiquitylation by the von Hippel Lindau (VHL)2 protein that acts as its E3 ligase [4]
Whereas the above described mechanism provides a tight control of HIF-␣ levels under normoxic conditions, little is known about the mechanisms that may control the fate of HIF-␣ proteins in hypoxic cells
Most proteins that are degraded by the proteasome system need first to be ubiquitylated, but there are several examples of proteins, including transcription factors that are degraded by the proteasome without prior ubiquitylation [16, 17]

Summary

Introduction

15498 JOURNAL OF BIOLOGICAL CHEMISTRY ubiquitylation by the von Hippel Lindau (VHL)2 protein that acts as its E3 ligase [4]. We report that in addition to the canonical oxygen and VHL-dependent pathway, HIF proteins (HIF-1␣ and HIF-2␣) are constitutively degraded by the proteasome system utilizing an oxygen, VHL, and ubiquitin-independent mechanism. This last mechanism appears to be independent of the formation of HIF-1 complexes, DNA binding, or the transactivating activity of the protein and likely utilizes the 20S proteasome for degradation.

Results

Conclusion